Reviewing Traditional and Novel Approaches to Managing Anemia of Chronic Kidney Disease
DOI:
https://doi.org/10.61173/w5ma9615Keywords:
anemia, chronic kidney disease, erythropoietin, iron homeostasis, erythropoiesis-stimulating agents, hypoxia-inducible factor prolyl hydroxylase inhibitorsAbstract
Anemia is a common complication of chronic kidney disease (CKD). If not managed appropriately, anemia can be highly debilitating and potentially life-threatening for CKD patients. Various treatments have been developed to alleviate CKD-associated anemia, with the main goals of restoring circulating iron, promoting erythropoiesis, and downregulating hepcidin. Mainstream treatment options include iron supplements, erythropoiesis-stimulating agents (ESAs), hepcidin antagonists, and blood transfusion. However, the therapeutic efficacy of current CKD anemia treatments is hindered by extensive adverse effects, most notably iron overload and ESA resistance. HIF-PH (hypoxia-induced factor prolyl hydroxylase) inhibitors are a novel class of orally bioavailable drugs for CKD anemia. HIF-PH inhibitors adopt a distinct mechanism, stimulating erythropoiesis via transcriptional regulation of the hypoxia-activated erythropoietin (EPO) gene. This review summarizes existing and emerging therapeutic strategies for CKD-associated anemia, with particular emphasis on HIF-PH inhibitors and their clinical potential and risks.
References
[1] McGonigle, R. J., Wallin, J. D., Shadduck, R. K., & Fisher, J. W. (1984). Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney international, 25(2), 437–444. https://doi.org/10.1038/ki.1984.36
[2] Besarab A, Ayyoub F: Anemia in renal disease. In: Diseases of the Kidney and Urinary Tract, edited by Schrier RW, 8th Ed., Philadelphia, Lippincott Williams and Wilkins, 2007, pp 2406– 2430 (Journal of the American Society of Nephrology (lww. com) 23)
[3] Yang, Ju-Yeh*,†; Lee, Tsung-Chun‡; Montez-Rath, Maria E.*; Paik, Jane§; Chertow, Glenn M.*; Desai, Manisha§; Winkelmayer, Wolfgang C.*. Trends in Acute Nonvariceal Upper Gastrointestinal Bleeding in Dialysis Patients. Journal of the American Society of Nephrology 23(3):p 495-506, March
[2012] | DOI: 10.1681/ASN.2011070658
[4] Firkin F, Rush B. Interpretation of biochemical tests for iron deficiency: diagnostic difficulties related to limitations of individual tests. Aust Prescr 1997;20:74-6.https://doi. org/10.18773/austprescr.1997.063
[5] Ueda N, Takasawa K. Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease. Nutrients. 2018; 10(9):1173. https:// doi.org/10.3390/nu10091173
[6] Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2023. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2023. Chronic Kidney Disease in the United States, 2023 | Chronic Kidney Disease | CDC
[7] Stauffer ME, Fan T (2014) Prevalence of Anemia in Chronic Kidney Disease in the United States. PLoS ONE 9(1): e84943. https://doi.org/10.1371/journal.pone.0084943
[8] EPOR erythropoietin receptor [Homo sapiens (human)] - Gene - NCBI (nih.gov)
[9] Goldsmith D, Dellanna F, Schiestl M, Krendyukov A, Combe C. Epoetin Biosimilars in the Treatment of Renal Anemia: What Have We Learned from a Decade of European Experience? Clin Drug Investig. 2018 Jun;38(6):481-490. doi: 10.1007/s40261- 018-0637-1. PMID: 29500617; PMCID: PMC5951862.
[10] Portolés J. et al. (2021) Anemia in chronic kidney disease: From pathophysiology and current treatments to future agents, Frontiers in Medicine, 8. doi:10.3389/fmed.2021.642296.
[11] Smirnov, I. V., Vorobiev, I. I., Belogurov, A. A., Genkin, D. D., Deyev, S. M., & Gabibov, A. G. (2015). Chemical Polysialylation of Recombinant Human Proteins. Methods in molecular biology (Clifton, N.J.), 1321, 389–404. https://doi. org/10.1007/978-1-4939-2760-9_26
[12] Elliott S, Tomita D, Endre Z. Erythropoiesis stimulating agents and reno-protection: a meta-analysis. BMC Nephrol. 2017 Jan 11;18(1):14. doi: 10.1186/s12882-017-0438-4. PMID: 28077085; PMCID: PMC5225567.
[13] Wu, H. H. L., Chinnadurai R. Erythropoietin-Stimulating Agent Hyporesponsiveness in Patients Living with Chronic Kidney Disease. Kidney Dis (Basel). 2022 Jan 14;8(2):103-
[114] doi: 10.1159/000521162. PMID: 35527989; PMCID: PMC9021651.
[14] Rottembourg, J., & Rostoker, G. (2015). Utilisation des dérivés injectables du fer au cours de la maladie rénale chronique : intérêts, limites et conseils pour un bon usage [Use of intravenous iron supplementation in chronic kidney disease: Interests, limits, and recommendations for a better practice]. Nephrologie & therapeutique, 11(7), 531–542. https:// doi.org/10.1016/j.nephro.2015.04.009
[15] van der Weerd, N. C., Grooteman, M. P., Nubé, M. J., ter Wee, P. M., Swinkels, D. W., & Gaillard, C. A. (2015). Hepcidin in chronic kidney disease: not an anaemia management tool, but promising as a cardiovascular biomarker. The Netherlands journal of medicine, 73(3), 108–118.
[16] DeLoughery, T.G. (2019). Safety of oral and intravenous iron. Acta Haematologica, 142(1), pp. 8–12. doi:10.1159/000496966.
[17] Shih, H.-M., Wu, C.-J. and Lin, S.-L. (2018). Physiology and pathophysiology of renal erythropoietin-producing cells, Journal of the Formosan Medical Association, 117(11), pp. 955–963. doi:10.1016/j.jfma.2018.03.017.
[18] Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., Dean&Francis ISSN 2959-409X & Pouysségur, J. (2003). HIF prolyl‐hydroxylase 2 is the key oxygen sensor setting low steady‐state levels of HIF‐1α in normoxia. The EMBO journal. Berra: HIF prolyl‐hydroxylase 2 is the key oxygen... - Google Scholar
[19] Chen, N., Qian, J., Chen, J., Yu, X., Mei, C., Hao, C., Jiang, G., Lin, H., Zhang, X., Zuo, L., He, Q., Fu, P., Li, X., Ni, D., Hemmerich, S., Liu, C., Szczech, L., Besarab, A., Neff, T. B., Peony Yu, K. H., … Valone, F. H. (2017). Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG- 4592 for treatment of anemia in China. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 32(8), 1373–1386. https://doi.org/10.1093/ndt/gfx011
[20] Zheng, Q., Wang, Y., Yang, H., Sun, L., Zhang, P., Zhang, X., Guo, J., Liu, Y. N., & Liu, W. J. (2023). Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis. American journal of kidney diseases : the official journal of the National Kidney Foundation, 81(4), 434–445.e1. https://doi.org/10.1053/ j.ajkd.2022.09.014
[21] Macdougall, I. C., Akizawa, T., Berns, J. S., Bernhardt, T., & Krueger, T. (2019). Effects of Molidustat in the Treatment of Anemia in CKD. Clinical journal of the American Society of Nephrology : CJASN, 14(1), 28–39. https://doi.org/10.2215/ CJN.02510218
[22] Fukuta, H., Hagiwara, H., & Kamiya, T. (2022). Hypoxiainducible factor prolyl hydroxylase inhibitors for anemia in heart failure patients: A protocol for systematic review and metaanalysis. PloS one, 17(9), e0275311. https://doi.org/10.1371/ journal.pone.0275311
[23] Li Y, Zhao L, Li X-F. Hypoxia and the Tumor Microenvironment. Technology in Cancer Research & Treatment. (2021). 20. doi:10.1177/15330338211036304
[24] Kunz, M., & Ibrahim, S. M. (2003). Molecular responses to hypoxia in tumor cells. Molecular cancer, 2, 23. https://doi. org/10.1186/1476-4598-2-23
[25] Liu H, Li Y, Xiong J. The Role of Hypoxia-Inducible Factor-1 Alpha in Renal Disease. Molecules. 2022; 27(21):7318. https://doi.org/10.3390/molecules27217318
[26] Gale, D. P., Harten, S. K., Reid, C. D., Tuddenham, E. G., & Maxwell, P. H. (2008). Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 α mutation. Blood, The Journal of the American Society of Hematology, 112(3), 919-921.
[27] Pak, O., Aldashev, A., Welsh, D., & Peacock, A. (2007). The effects of hypoxia on the cells of the pulmonary vasculature. European Respiratory Journal, 30(2), 364-372.
[28] Ribatti D. Tumor refractoriness to anti-VEGF therapy. Oncotarget. 2016; 7: 46668-46677. https://doi.org/10.18632/ oncotarget.8694
[29] programmed death ligand 1. IUPHAR/BPS Guide to Pharmacology. 2024. Available from: programmed cell death 1 ligand 1 | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY
[30] Kaelin, William G. et al. (2008). Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway. Molecular Cell, 30(4), 393 – 402. Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway: Molecular Cell
Downloads
Published
Issue
Section
License
Copyright (c) 2026 by the authors.
This work is licensed under a Creative Commons Attribution 4.0 International License.
